Abnormal increase of concentrations of lipids in plasma is called "hyperlipidemia" or "hyperlipemia". Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipid (lecithin, sphingomyelin, etc.), triglyceride (neutral fat), free fatty acid and other sterols. Increase of cholesterol and triglyceride is especially taken up as a problem from the clinical viewpoint [cf. Common Disease Series No.19 Koshikessho (hyperlipemia) compiled by Haruo Nakamura, published by Nankodo].
Therefore, adequate control of lipid concentration in blood is remarkably important for the prophylaxis or therapy of various diseases related to arteriosclerosis typically exemplified by ischemic heart disease and cerebral infarction. And, hypertriglyceridemia is considered to accompany pancreatic disorders.
As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (for example, U.S. Pat. No. 4,027,009), and those of suppressing the intestinal absorption of cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (French Patent No.1476569). As pharmaceutical preparations for controlling the biosynthesis of cholesterol, lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for medicinal use. However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.
While, as agents of lowering triglyceride, fibrinoic acid type compounds, for example, clofibrate (UK Patent 860303) and fenofibrate (German Patent 2250327), are provided for medicines, they are prohibited to use together with statin type compounds for the fear of causing liver-toxicity.
Squalene synthetase is an enzyme taking part in the essential stage of the cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.
On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in Journal of Medicinal Chemistry, Vol.51, No.10, pp.1869-1871, 1988, JPA H1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPA H3(1991)-148288, and U.S. Pat. Nos. 5,019,390, 5,135,935, WO9215579 and WO9309115.
Incidentally, hyperlipemia is also called "hyperlipoproteinemia" and is classified into the following six types (WHO classification) taking lipoproteins into consideration.
Type I: hyperchylomicronemia showing increase of chylomicrons, PA0 Type IIa: hyperLDLemia (hypercholesterolemia) showing increase of low-density lipoprotein (LDL), PA0 Type IIb: composite hyperlipemia showing increase of LDL and very-low-density lipoprotein (VLDL), PA0 Type III: abnormal .beta. lipoproteinemia showing the presence of .beta. very-low-density lipoprotein (.beta. VLDL), PA0 Type IV: endogenous hypertriglycerolemia, and PA0 Type V: mixed type hyperlipemia showing increase of VLDL and chylomicrons. PA0 (1) a compound represented by the formula (I) ##STR2## wherein R stands for a lower alkyl group optionally substituted by hydroxyl group which may be substituted, X stands for an optionally substituted carbamoyl group or an optionally substituted heterocyclic group having a deprotonatable hydrogen atom, R.sub.1 stands for a lower alkyl group and W stands for a halogen atom, or a salt thereof, PA0 (2) the compound of (1) defined above, wherein R is C.sub.1-6 alkyl which may have 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, PA0 (3) the compound of (1) defined above, wherein R is C.sub.3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, PA0 (4) the compound of (1) defined above, wherein R is 2,2-dimethyl-3-hydroxypropyl, 3-hydroxy-2-hydroxymethyl-2-methylpropyl, 3-acetoxy-2,2-dimethylpropyl, 3-acetoxy-2-hydroxymethyl-2-methylpropyl or 3-acetoxy-2-acetoxymethyl-2-methylpropyl, PA0 (5) the compound of (1) defined above, wherein R.sub.1 is methyl, PA0 (6) the compound of (1) defined above, wherein W is chlorine atom, PA0 (7) the compound of (1) defined above, wherein X is a carbamoyl group represented by the formula ##STR3## wherein R.sub.2 and R.sub.3 are independently (i) hydrogen, PA0 (8) the compound of (7) defined above, wherein R.sub.2 is hydrogen or C.sub.1-7 alkyl, R.sub.3 is PA0 1) a hydrocarbon group selected from the group consisting of PA0 2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl and 2,3-dihydro-3-thioxo-1,2,4-triazolyl or the salt thereof, PA0 3) an acyl group selected from the group consisting of PA0 (A) hydroxyl which may be substituted with C.sub.1-3 alkyl or C.sub.2-7 alkanoyl, PA0 (B) carboxyl which may be substituted with C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, PA0 (C) phosphono which may be mono- or di-substituted by C.sub.1-6 alkyl or C.sub.2-7 alkanoyloxy-C.sub.1-6 alkyl, PA0 (D) sulfo, PA0 (E) sulfonamide which may be substituted with C.sub.1-6 alkyl or C.sub.6-10 aryl-C.sub.1-4 alkyl, PA0 (F) C.sub.1-6 alkyl or C.sub.2-5 alkenyl which may be substituted by PA0 (G) amino which may be mono- or di-substituted with C.sub.1-3 alkyl, PA0 (H) cyclic amino group selected from the group consisting of piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, and 4-phenyl-piperazinyl, PA0 (I) cyano, PA0 (J) carbamoyl, PA0 (K) oxo, PA0 (L) heterocyclic group selected from tetrazolyl and 2,5-dihydro-5-oxo-1,2,4-oxadiazolyl, PA0 (M) carbamoyl substituted with C.sub.1-4 alkylsulfonyl, C.sub.6-10 arylsulfonyl or C.sub.6-10 aryl-C.sub.1-4 alkylsulfonyl, PA0 (N) sulfhydryl which may be alkylated with C.sub.1-3 alkyl, PA0 (O) phenyl which may have 1 to 5 substituents selected from hydroxyl, halogen, aminosulfonyl and amino which may be substituted with C.sub.1-3 alkyl, or the salt thereof, PA0 (9) the compound of (7) defined above, wherein R.sub.2 and R.sub.3 together with the adjacent nitrogen of the carbamoyl form a 5 to 6-membered ring selected from the group consisting of 1-piperazinyl, piperidyl, 1-pyrrolidinyl, 2-oxo-piperazinyl and 2,6-dioxo-piperazinyl, each of the said group may have 1 to 2 substituents of C.sub.1-6 alkyl which may be substituted by PA0 (10) the compound of (7) defined above, wherein R.sub.2 is hydrogen or C.sub.1-7 alkyl and R.sub.3 is C.sub.1-4 alkylsulfonyl, PA0 (11) The compound of term (1) defined above, wherein the heterocyclic group represented by X is tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl, or 2,3-dihydro-3-thioxo-1,2,4-triazolyl, PA0 (12) the compound of (1) defined above, wherein PA0 (13) the compound of (1) defined above, wherein PA0 (14) the compound of (1) defined above, wherein PA0 R.sub.1 is methyl, W is chlorine atom, PA0 R is C.sub.3-6 branched alkyl which has 1 to 3 substituents selected from the group consisting of hydroxyl, acetyloxy, propionyloxy, t-butoxycarbonyloxy, palmitoyloxy, dimethylaminoacetyloxy and 2-aminopropionyloxy, and X is tetrazolyl, PA0 (16) the compound of (1) defined above, which is PA0 (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2 -dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, PA0 (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-h ydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-a cetamide, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-met hylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzox azepine-3-acetamide, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2 -oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-acet amide, or a salt thereof, PA0 (17) the compound of (1) defined above, which is PA0 (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3- dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, PA0 (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-ch loro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-a cetamide, PA0 N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl )-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, PA0 N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dim ethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin e-4-acetic acid, PA0 N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl )-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester, PA0 N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dim ethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin e-4-acetic acid ethyl ester or a salt thereof, PA0 (18) the compound of (1) defined above, which is PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1 ,2,3,5-tetrahydro-3-[1H(or3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-met hylpropyl)-1,2,3,5-tetrahydro-3-[1H(or3H)-tetrazol-5-yl]methyl-4,1-benzoxaz epine-2-one, PA0 (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-1 ,2,3,5-tetrahydro-3-[1H(or3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, PA0 (3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimeth oxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or3H)-tetrazol-5-yl]methyl-4,1-benzoxaz epine-2-one or a salt thereof, PA0 (19) the compound of (1) defined above, which is PA0 (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolidin -1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or the salt thereof, PA0 (20) the compound of (1) defined above, wherein PA0 R is a lower alkyl group which may be substituted with one or two hydroxyl groups, PA0 X is carbamoyl group, which may have substituent(s) on the nitrogen atom of the carbamoyl group, PA0 (1) hydrocarbon selected from the group consisting of PA0 (2) a heterocyclic group selected from the group consisting of tetrazolyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazolyl, 4,5-dihydro-5-thioxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-oxadiazolyl, 2,3-dihydro-3-thioxo-1,2,4-oxadiazolyl, 3,5-dioxo-1,2,4-oxadiazolidinyl, 4,5-dihydro-5-oxo-isoxazolyl, 4,5-dihydro-5-thioxo-isoxazolyl, 2,3-dihydro-2-oxo-1,3,4-oxadiazolyl, 2,3-dihydro-3-oxo-1,2,4-triazolyl and 2,3-dihydro-3-thioxo-1,2,4-triazolyl, PA0 (3) an acyl group selected from the group consisting of PA0 (4) cyclic amino carbonyl group, the cyclic amino group being selected from the group consisting of piperazinyl, piperidyl, pyrrolidinyl, 2-oxo-piperazinyl, 2,6-dioxopiperazinyl, morpholinyl and thiomorpholinyl, PA0 (21) a composition which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier, PA0 (22) a pharmaceutical composition for inhibiting squalene synthetase, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier, PA0 (23) a pharmaceutical composition for lowering the level of triglyceride, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier, PA0 (24) a pharmaceutical composition for lowering the lipid-level, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier, PA0 (25) a pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia, which comprises the compound of (1) defined above and a pharmaceutically acceptable carrier, PA0 (26) use of the compound of (1) defined above for manufacturing a pharmaceutical composition, PA0 (27) use of the compound of (1) defined above for manufacturing a squalene synthetase inhibitor, PA0 (28) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for lowering the level of triglyceride, PA0 (29) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for lowering the lipid-level, PA0 (30) use of the compound of (1) defined above for manufacturing a pharmaceutical composition for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis, PA0 (31) a method for inhibiting squalene synthetase in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal, PA0 (32) a method for lowering the level of triglyceride in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal, PA0 (33) a method for lowering the lipid-level in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal, PA0 (34) a method for prophylaxis or therapy of hyperlipidaemia or coronary sclerosis in a mammal comprising administering an effective amount of the compound of (1) defined above to said mammal, PA0 (35) a process for producing the compound or the salt thereof of (1) defined above, wherein X is an optionally substituted carbamoyl group, which comprises reacting a compound of the formula: ##STR7## wherein the symbols are the same as defined in term (1), or a salt thereof with a compound of the formula: ##STR8## wherein the symbols are the same as defined in (7), or a salt thereof, (36) the compound of (1) defined above, wherein R is 2,2-dimethyl-3-hydroxypropyl. PA0 (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2 -dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, PA0 (3R,5S)-N-methanesulfonyl-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-h ydroxymethyl-2-methylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-a cetamide, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-met hylpropyl)-2-oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzox azepine-3-acetamide, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2 -oxo-N-[2-(pyrrolidin-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzazepine-3-acet amide, PA0 (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3- dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, PA0 (3R,5S)-N-methanesulfonyl-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-ch loro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-a cetamide, PA0 N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl )-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid, PA0 N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dim ethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin e-4-acetic acid, PA0 N-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl )-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidine-4-acetic acid ethyl ester, PA0 N-[(3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dim ethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetyl]piperidin e-4-acetic acid ethyl ester, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-1 ,2,3,5-tetrahydro-3-[1H(or 3H)tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, PA0 (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2-hydroxymethyl-2-met hylpropyl)-1,2,3,5-tetrahydro-3-[1H(or3H)-tetrazol-5-yl]methyl-4,1-benzoxaz epine-2-one, PA0 (3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl-7-chloro-5-(2,3-dimethoxyphenyl)-1, 2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, PA0 (3R,5S)-1-(3-acetoxy-2-acetoxymethyl-2-methylpropyl)-7-chloro-5-(2,3-dimeth oxyphenyl)-1,2,3,5-tetrahydro-3-[1H(or 3H)-tetrazol-5-yl]methyl-4,1-benzoxazepine-2-one, (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-N-[2-(pyrrolidi n-1-yl)ethyl]-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide, etc. PA0 Medicines for diabetes mellitus: kinedak, benfil, humulin, euglucon, glimicron, daonil, novorin, monotard, insulins, glucobay, dimelin, rastinon, bacilcon, deamiline S, iszilins; PA0 Medicines for hypothyroidism: thyroid (thyreoid), levothyroxine sodium (thyradin S), liothyronine sodium (cylonine, cylomin); PA0 Medicines for nephrotic syndrome: For the therapy using steroid as the first choice, use is made of, for example, predinisolone sodium succinate (predonine), prednisolone sodium succinate (predonine), methyl prednisolone sodium succinate (solu-medrol) and betamethasone (renderon). And, for anticoagulant therapy, use is made of antiplatelet medicines such as dipyridamole (persantine) and dilazep hydrochloride (comelian); PA0 Medicines for chronic renal failure: A combination of diuretics [e.g. furosemide (lasix), bumetanide (lunetoron) and azosemide (diart)], hypotensive drugs (e.g. ACE inhibitors (enalapril maleate (renivace)) and Ca antagonists (Ca antagonistic drugs (maninhilone), .alpha.-receptor blocking agents is administered, preferably, orally. PA0 Medicines for prophylaxis and therapy of thrombus formation: blood coagulation inhibitors [e.g. heparin sodium, heparin calcium, warfarin calcium (warfarin)], thrombolytic agents [e.g. urokinase], antiplatelet agents [e.g. aspirin, sulfinpyrazolo(anturane), dipyridamole (persantine), acropidin (panaldin), cilostazol (pletaal)].